Targeting of the PI3 K/AKT/GSK3β Pathway in Parkinson's Disease: A Therapeutic Blueprint

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor and non-motor symptoms. PD neuropathology is due to the progressive deposition of mutant alpha-synuclein (α-Syn) in the dopaminergic neurons of the substantia nigra pars compacta (SNpc). This effect initiates oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis of the dopaminergic neurons in the SNpc. PD neuropathology, which is closely associated with inflammatory and oxidative disorders, disrupts different vital cellular pathways. Notably, the current anti-PD medications only relieve the symptoms of PD without averting the underlying neuropathology. Thus, it is advisable to search for novel drugs that attenuate the progression of PD neuropathology. It has been shown that phosphatidylinositol 3-kinase (PI3K), AKT, and glycogen synthase kinase 3 beta (GSK3β) signaling pathways are affected in PD. PI3K/AKT pathway is neuroprotective against the development and progression of PD. However, the over-activated GSK3β signaling pathway has a detrimental effect on PD neuropathology by inducing inflammation and oxidative stress. Dysregulation of the PI3K/AKT/GSK3β signaling pathway provokes brain insulin resistance (BIR), neuroinflammation, and neuronal apoptosis, the hallmarks of PD and other neurodegenerative diseases. However, the mechanistic role of the PI3K/AKT/GSK3β signaling pathway is not fully clarified. Therefore, in this review, we intend to discuss the role of the PI3K/AKT/GSK3β signaling pathway in PD pathogenesis and how PI3K/AKT activators and GSK3β inhibitors have helped effectively manage PD.

Keywords: Brain insulin resistance; Glycogen synthase kinase 3 beta; Lithium; Metformin; Neuroinflammation; Neuroprotection; Parkinson's disease; Phosphatidylinositol 3-kinase.